TY - JOUR
T1 - Mural cell-derived chemokines provide a protective niche to safeguard vascular macrophages and limit chronic inflammation
AU - Pekayvaz, Kami
AU - Gold, Christoph
AU - Hoseinpour, Parandis
AU - Engel, Anouk
AU - Martinez-Navarro, Alejandro
AU - Eivers, Luke
AU - Coletti, Raffaele
AU - Joppich, Markus
AU - Dionísio, Flávio
AU - Kaiser, Rainer
AU - Tomas, Lukas
AU - Janjic, Aleksandar
AU - Knott, Maximilian
AU - Mehari, Fitsumbirhan
AU - Polewka, Vivien
AU - Kirschner, Megan
AU - Boda, Annegret
AU - Nicolai, Leo
AU - Schulz, Heiko
AU - Titova, Anna
AU - Kilani, Badr
AU - Lorenz, Michael
AU - Fingerle-Rowson, Günter
AU - Bucala, Richard
AU - Enard, Wolfgang
AU - Zimmer, Ralf
AU - Weber, Christian
AU - Libby, Peter
AU - Schulz, Christian
AU - Massberg, Steffen
AU - Stark, Konstantin
PY - 2023/10/10
Y1 - 2023/10/10
N2 - Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages. Intravital imaging revealed a spatiotemporal macrophage niche across vascular beds alongside mural cells (MCs)-pericytes and smooth muscle cells. Single-cell transcriptomics, co-culture, and genetic deletion experiments revealed MC-derived expression of the chemokines CCL2 and MIF, which actively preserved macrophage survival and their homeostatic functions. In atherosclerosis, this positioned macrophages in viable plaque areas, away from the necrotic core, and maintained a homeostatic macrophage phenotype. Disruption of this MC-macrophage unit via MC-specific deletion of these chemokines triggered detrimental macrophage relocalizing, exacerbated plaque necrosis, inflammation, and atheroprogression. In line, CCL2 inhibition at advanced stages of atherosclerosis showed detrimental effects. This work presents a MC-driven safeguard toward maintaining the homeostatic vascular macrophage niche.
AB - Maladaptive, non-resolving inflammation contributes to chronic inflammatory diseases such as atherosclerosis. Because macrophages remove necrotic cells, defective macrophage programs can promote chronic inflammation with persistent tissue injury. Here, we investigated the mechanisms sustaining vascular macrophages. Intravital imaging revealed a spatiotemporal macrophage niche across vascular beds alongside mural cells (MCs)-pericytes and smooth muscle cells. Single-cell transcriptomics, co-culture, and genetic deletion experiments revealed MC-derived expression of the chemokines CCL2 and MIF, which actively preserved macrophage survival and their homeostatic functions. In atherosclerosis, this positioned macrophages in viable plaque areas, away from the necrotic core, and maintained a homeostatic macrophage phenotype. Disruption of this MC-macrophage unit via MC-specific deletion of these chemokines triggered detrimental macrophage relocalizing, exacerbated plaque necrosis, inflammation, and atheroprogression. In line, CCL2 inhibition at advanced stages of atherosclerosis showed detrimental effects. This work presents a MC-driven safeguard toward maintaining the homeostatic vascular macrophage niche.
KW - CCL2
KW - MIF
KW - atherosclerosis
KW - chemokines
KW - chronic inflammation
KW - macrophages
KW - mural cells
KW - pericytes
KW - smooth muscle cells
KW - vascular macrophages
U2 - 10.1016/j.immuni.2023.08.002
DO - 10.1016/j.immuni.2023.08.002
M3 - Article
SN - 1097-4180
VL - 56
SP - 2325-2341.e15
JO - Immunity
JF - Immunity
IS - 10
ER -